Glycation (sometimes called non-enzymatic glycosylation) is the result of a sugar molecule, such as fructose or glucose, bonding to a protein or lipid molecule without the controlling action of an enzyme. Glycation may occur either inside the body (endogenous glycation) or outside the body (exogenous glycation). Enzyme-controlled addition of sugars to protein or lipid molecules is termed glycosylation; glycation is a haphazard process that impairs the functioning of biomolecules, whereas glycosylation occurs at defined sites on the target molecule and is required in order for the molecule to function.
Exogenous glycations may also be referred to as dietary or pre-formed. Exogenous glycations and advanced glycation endproducts (AGEs) are typically formed when sugars are cooked with proteins or fats. Temperatures over 120° C. (˜248° F.) greatly accelerate the reactions, but lower temperatures with longer cooking times also promote their formation.
These compounds are absorbed by the body during digestion with about 30% efficiency. Browning reactions are evidence of pre-formed glycations. Sugar is often added to products such as french fries and baked goods to enhance browning. Until recently, it was thought that exogenous glycations and AGEs were negligible contributors to inflammation and disease states, but recent work has shown that they are important. Although most of the research work has been done with reference to diabetes, these results are most likely important for all people, as exogenous AGEs are implicated in the initiation of retinal dysfunction, cardiovascular diseases, type II diabetes, and many other age-related chronic diseases.
Food manufacturers have added AGEs to foods, especially in the last 50 years, as flavor enhancers and colorants to improve appearance. Foods with significant browning, caramelization, or with directly added preformed AGEs can be exceptionally high in these pro-inflammatory and disease initiating compounds. A very partial listing of foods with very high exogenous AGEs includes: donuts, barbecued meats, cake, and dark colored fizzy drinks.
Endogenous glycations occur mainly in the bloodstream to a small proportion of the absorbed simple sugars: glucose, fructose, and galactose. The balance of the sugar molecules is used for metabolic processes. It appears that fructose and galactose have approximately ten times the glycation activity of glucose, the primary body fuel. Glycation is the first step in the evolution of these molecules through a complex series of very slow reactions in the body known as Amadori reactions, Schiff base reactions, and Maillard reactions, all leading to advanced glycation endproducts. Some AGEs are benign, but others are more reactive than the sugars they are derived from, and are implicated in many age-related chronic diseases such as: type II diabetes mellitus (beta cell damage), cardiovascular diseases (the endothelium, fibrinogen, and collagen are damaged), Alzheimer's disease (amyloid proteins are side-products of the reactions progressing to AGEs), cancer (acrylamide and other side-products are released), peripheral neuropathy (the myelin is attacked), and other sensory losses such as deafness (due to demyelination) and blindness (mostly due to microvascular damage in the retina). This range of diseases is the result of the very basic level at which glycations interfere with molecular and cellular functioning throughout the body and the release of highly-oxidizing side-products such as hydrogen peroxide.
Glycated substances are eliminated from the body slowly, since the renal clearance factor is only about 30%. This implies that the half-life of a glycation within the body is about double the average cell life. Red blood cells are the shortest-lived cells in the body (120 days), so the half-life is about 240 days. This fact is used in monitoring blood sugar control in diabetes by monitoring the glycated hemoglobin level. As a consequence, long-lived cells (such as nerves, brain cells), long-lasting proteins (such as eye crystalline and collagen), and DNA may accumulate substantial damage over time. Metabolically-active cells such as the glomeruli in the kidneys, retina cells in the eyes, and beta cells (insulin-producing) in the pancreas are also at high risk of damage. The epithelial cells of the blood vessels are damaged directly by glycations, which are implicated in atherosclerosis, for example. Atherosclerotic plaque tends to accumulate at areas of high blood flow (such as the entrance to the coronary arteries) due to the increased presentation of sugar molecules, glycations and glycation end-products at these points. Damage by glycation results in stiffening of the collagen in the blood vessel walls, leading to high blood pressure. Glycations also cause weakening of the collagen in the blood vessel walls, which may lead to micro- or macro-aneurisms; this may cause strokes if in the brain.
The USA, New Zealand and many developed nations are facing a dangerous epidemic of type 2 diabetes. In the US, there are an estimated 20.6 million people with diabetes and 30% are undiagnosed. Another 54 million people have some form of pre-diabetes and many will develop into diabetes within three years.
Diagnosis of diabetes is typically initiated during a physical examination by a primary care physician. Screening for type 2 diabetes and pre-diabetes is inadequate. The most widely used test, the fasting plasma glucose (FPG) test, requires the subject to fast overnight before being subjected to a blood draw. The sensitivity is poor (40-60%). Currently, around 50% of patients diagnosed with diabetes already have one or more irreversible complications due to untreated diabetes.
International patent application WO 2005/045393 discloses a non-invasive method of determining a measure of glycation end-product or disease state using tissue fluorescence. A portion of the tissue of an individual is illuminated with excitation light then light emitted by the tissue due to fluorescence of certain chemicals (mainly AGEs) is detected. The detected light can be combined with a model relating fluorescence with a disease state to determine the disease state of an individual. Various correction techniques are employed to reduce determination errors due to detection of light other than that from fluorescence of a chemical in the tissue. For example, background fluorescence of the skin based on the individuals biological information can affect the measure of AGEs. This adds to the complexity of the test device.
This test device is very similar to a test device being developed by VeraLight in Albuquerque, N. Mex., USA. This uses five different excitation wavelengths of light between 350 nm and 450 nm and measures the spectrum of fluorescence from each of the five excitation wavelengths of light. The information is then analyzed with principal component analysis, with the object of separating the fluorescence of the GPs from other fluorescence in the skin, and quantifying the amount of GPs.